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The role of HYAL2 in LSS-induced glycocalyx impairment and the PKA-mediated decrease in eNOS-Ser-633 phosphorylation
Xiangquan Kong1,2, Liang Chen1, Peng Ye1
1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210001, China.
Molecular Biology of the Cell
|November 1, 2016
Summary
Low shear stress activates hyaluronidase 2 (HYAL2) to degrade hyaluronan (HA) in the endothelial glycocalyx. This impairs nitric oxide (NO) production by affecting endothelial nitric oxide synthase (eNOS) phosphorylation.
Area of Science:
- Endothelial biology
- Mechanotransduction
- Molecular signaling
Background:
- Hyaluronan (HA) in the endothelial glycocalyx is crucial for mechanotransduction, mediating responses to shear stress.
- Low shear stress (LSS) impairs glycocalyx integrity, contributing to endothelial dysfunction, inflammation, and atherosclerosis.
- Endothelial nitric oxide synthase (eNOS) phosphorylation is vital for nitric oxide (NO) production.
Purpose of the Study:
- To investigate the role of hyaluronidase 2 (HYAL2) in LSS-induced glycocalyx impairment.
- To determine the impact of HYAL2-mediated HA degradation on eNOS phosphorylation and NO production.
- To elucidate the signaling pathway involving HYAL2, PKA, and eNOS under LSS.
Main Methods:
- Utilized human umbilical vein endothelial cells (HUVECs).
- Applied low shear stress (LSS) to induce cellular responses.
- Assessed HYAL2 activation, HA degradation, eNOS-Ser-633 phosphorylation, and NO production.
- Employed HYAL2 knockdown (siRNA) and PKA activator (8-Br-cAMP) for mechanistic studies.
Main Results:
- LSS significantly activated HYAL2, leading to HA degradation within the glycocalyx.
- HA degradation by HYAL2 was linked to the dephosphorylation of eNOS-Ser-633 and reduced NO production.
- Knocking down HYAL2 protected the glycocalyx, preserved eNOS phosphorylation, and maintained NO levels under LSS.
- LSS-induced dephosphorylation of PKA was abrogated in HYAL2-deficient cells, and PKA activation reversed eNOS dephosphorylation.
Conclusions:
- LSS promotes endothelial dysfunction by activating HYAL2, which degrades HA in the glycocalyx.
- This degradation process leads to impaired eNOS phosphorylation and reduced NO bioavailability.
- Targeting HYAL2 may offer a therapeutic strategy to mitigate LSS-induced endothelial dysfunction.
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